Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

Isovitexin restores sevoflurane­induced cognitive dysfunction by mediating autophagy through activation of the PGC­1α/FNDC5 signaling pathway.

Postoperative cognitive dysfunction is a severe neurological complication. How to improve the cognitive impairment caused by sevoflurane, a most common inhaled anesthetic, remains a question worthy of studying. Isovitexin (IVX) is a trihydroxyl flavonoid that is a naturally bioactive ingredient found in various medicinal plants and has antioxidant, anti­inflammatory and neuroprotective properties. The role of IVX in anesthetic­induced nerve injury is rarely reported and the mechanisms are unclear. In this study, we found that IVX improved the cognitive dysfunction induced by sevoflurane in rats. It inhibited sevoflurane­induced cell apoptosis. In addition, IVX increased sevoflurane­induced autophagy in rat brain. Mechanically, IVX activated the PGC­1α/FNDC5 pathway in rat brain, and depletion of FNDC5 could inhibit the neuroprotective function of IVX. In conclusion, our results suggested that IVX restored sevoflurane­induced cognitive dysfunction by mediating autophagy through the activation of the PGC­1α/FNDC5 pathway.

Optimization of Ultrasound Backscatter Spectroscopy to Assess Neurotoxic Effects of Anesthesia in the Newborn Non-human Primate Brain.

Studies in animal models have revealed that long exposures to anesthetics can induce apoptosis in the newborn and young developing brain. These effects have not been confirmed in humans because of the lack of a non-invasive, practical in vivo imaging tool with the ability to detect these changes. Following the successful use of ultrasound backscatter spectroscopy (UBS) to monitor in vivo cell death in breast tumors, we aimed to use UBS to assess the neurotoxicity of the anesthetic sevoflurane (SEVO) in a non-human primate (NHP) model. Sixteen 2- to 7-day-old rhesus macaques were exposed for 5 h to SEVO. Ultrasound scanning was done with a phased array transducer on a clinical ultrasound scanner operated at 10 MHz. Data consisting of 10-15 frames of radiofrequency (RF) echo signals from coronal views of the thalamus were obtained 0.5 and 6.0 h after initiating exposure. The UBS parameter "effective scatterer size" (ESS) was estimated by fitting a scattering form factor (FF) model to the FF measured from RF echo signals. The approach involved analyzing the frequency dependence of the measured FF to characterize scattering sources and selecting the FF model based on a χ2 goodness-of-fit criterion. To assess data quality, a rigorous acceptance criterion based on the analysis of prevalence of diffuse scattering (an assumption in the estimation of ESS) was established. ESS changes after exposure to SEVO were compared with changes in a control group of five primates for which ultrasound data were acquired at 0 and 10 min (no apoptosis expected). Over the entire data set, the average measured FF at 0.5 and 6.0 h monotonically decreased with frequency, justifying fitting a single FF over the analysis bandwidth. χ2 values of a (inhomogeneous continuum) Gaussian FF model were one-fifth those of the discrete fluid sphere model, suggesting that a continuum scatterer model better represents ultrasound scattering in the young rhesus brain. After application of the data quality criterion, only 5 of 16 subjects from the apoptotic group and 5 of 5 subjects from the control group fulfilled the acceptance criteria. All subjects in the apoptotic group that passed the acceptance criterion exhibited a significant ESS reduction at 6.0 h. These changes (-6.4%, 95% Interquartile Range: -14.3% to -3.3%) were larger than those in the control group (-0.8%, 95% Interquartile Range: -2.0% to 1.5%]). Data with a low prevalence of diffuse scattering corresponded to possibly biased results. Thus, ESS has the potential to detect changes in brain microstructure related to anesthesia-induced apoptosis.

[Effect of transcutaneous electrical acupoint stimulation on postoperative olfactory memory disorder and plasma melatonin in patients with general anesthesia of sevoflurane].

OBJECTIVE: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative olfactory memory disorder in patients with general anesthesia of sevoflurane and to explore its possible mechanism. METHODS: Forty patients who were scheduled to have gynecological and urological procedures under general anesthesia were randomly divided into an observation group and a control group, 20 cases in each group. The patients in the observation group were treated with TEAS (dilatational wave, 2 Hz/100 Hz) at Yingxiang (LI 20) and Yintang (GV 29) 10 min before anesthesia induction until the end of operation; the patients in the control group received general anesthesia directly. The changes of mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were recorded before treatment, 30 min after operation and at the end of operation; smell identification score was measured by Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test before treatment (T0) and when Aldrete recovery score reached 10 points at the end of anesthesia (T1); the concentration of melatonin in plasma was measured by ELISA method in the two groups. RESULTS: The between-group differences and within-group differences of MAP, HR and SpO2 were not significant at each time point (P>0.05). Compared with T0, the score of smell identification and plasma concentration of melatonin were not significantly different at T1 in the observation group (P>0.05), however, the score of smell identification and plasma concentration of melatonin were reduced in the control group (P<0.05). At T1, the score of smell identification and plasma concentration of melatonin in the observation group were higher than those in the control group (P<0.05). CONCLUSION: TEAS could improve the postoperative olfactory memory disorder in patients with general anesthesia of sevoflurane, and its mechanism may be related to the increase of plasma concentration of melatonin.

Randomized controlled trial of acupuncture to prevent emergence delirium in children undergoing myringotomy tube placement.

BACKGROUND: Myringotomy tube placement is a pediatric procedure frequently performed under inhalational anesthesia without intravenous line placement. Emergence delirium is common following sevoflurane anesthesia, and can lead to patient harm and escalation of nursing care. Our goal was to determine if intraoperative acupuncture, compared to standard of care, reduces emergence delirium in children undergoing myringotomy tube placement. METHODS: Single center, randomized, controlled trial at a university hospital, including children ages 1-6 years with ASA physical status 1-3 scheduled for myringotomy tube placement. Participants were stratified based on midazolam premedication and randomized to intraoperative acupuncture (AC, N.=49) or standard anesthesia care (SC, N.=50). Acupuncture needles were placed in bilateral Heart 7 (HT7) and ear Shen Men points after anesthesia induction. A blinded observer in the PACU assessed emergence delirium using the Pediatric Anesthesia Emergence Delirium (PAED) scale. Endpoints were highest PAED score in the recovery room and post-discharge agitation and sleep quality. RESULTS: Patient baseline characteristics were similar between treatment groups. With midazolam premedication, the highest PAED score was 11.6 in patients receiving AC and 12.0 for SC. Without midazolam premedication, the highest PAED was 11.8 in patients receiving AC and 10.7 for SC. The overall PAED score difference between AC and SC groups was 0.33 (95% CI -1.5, 2.2, P=0.723). CONCLUSIONS: Intraoperative acupuncture at HT7 and ear Shen Men did not reduce PAED scores after myringotomy tube placement. Based on these data, it is therefore unlikely that a larger study of the same design would demonstrate a significant effect of intraoperative acupuncture on emergence delirium after brief sevoflurane anesthesia. However, other acupuncture points or techniques could be considered.

Pilose antler polypeptide protects against sevoflurane­mediated neurocyte injury.

Pilose antler polypeptide (PAP) is an active substance isolated from the traditional Chinese medicine pilose antler, which possesses multiple biological activities. In the present study, the role and mechanism of PAP in sevoflurane (SEV)­induced neurocyte injury was explored. Cell viability was determined by Cell Counting kit­8 assay. Cell proliferation and apoptosis were analyzed by flow cytometry. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were used to evaluate the protein and mRNA expression levels, respectively. The results revealed that PAP enhanced the cell viability of SEV­treated nerve cells. In addition, through modulation of apoptosis­associated protein expression, PAP suppressed SEV­induced nerve cell apoptosis. Furthermore, PAP activated the p38 mitogen­activated protein kinase (p38)/c­Jun N­terminal kinase (JNK) pathway in the neurocyte injury model, whereas inhibition of the p38/JNK pathway reversed the beneficial effects produced by PAP. In conclusion, PAP protected against SEV­mediated neurocyte injury via upregulation of the p38/JNK pathway. The present findings suggested that PAP may be an effective agent for neurocyte injury.